Regulation of lymphatic vascular morphogenesis: Implications for pathological - tumor lymphangiogenesis.

Feb 2013

Martinez-Corral I, Makinen T.

Source

Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

Abstract

Lymphatic vasculature forms the second part of our circulatory system that plays a critical role in tissue fluid homeostasis. Failure of the lymphatic system can lead to excessive accumulation of fluid within the tissue, a condition called lymphedema. Lymphatic dysfunction has also been implicated in cancer metastasis as well as pathogenesis of obesity, atherosclerosis and cardiovascular disease. Since the identification of the first lymphatic marker VEGFR-3 and growth factor VEGF-C almost 20 years ago, a great progress has been made in understanding the mechanisms of lymphangiogenesis. This has been achieved largely through characterization of animal models with specific lymphatic defects and identification of genes causative of human hereditary lymphedema syndromes. In this review we will summarize the current understanding of the regulation of lymphatic vascular morphogenesis, focusing on mechanisms that have been implicated in both developmental and pathological (tumor) lymphangiogenesis.

Elsevier

A pathway for unicellular tube extension depending on the lymphatic vessel determinant Prox1 and on osmoregulation.

Jan 2013

Kolotuev I, Hyenne V, Schwab Y, Rodriguez D, Labouesse M.

Source

1] IGBMC, Development and Stem Cells Program, CNRS (UMR7104)/INSERM (U964)/Université de Strasbourg, 1 rue Laurent Fries, BP.10142, 67400 Illkirch, France [2].

Abstract

The mechanisms regulating the extension of small unicellular tubes remain poorly defined. Here we identify several steps in Caenorhabditis elegans excretory canal growth, and propose a model for lumen extension. Our results suggest that the basal and apical excretory membranes grow sequentially: the former extends first like an axon growth cone; the latter extends next as a result of an osmoregulatory activity triggering peri-apical vesicles (a membrane reservoir) to fuse with the lumen. An apical cytoskeletal web including intermediate filaments and actin crosslinking proteins ensures straight regular lumengrowth. Expression of several genes encoding proteins mediating excretory lumen extension, such as the osmoregulatory STE20-like kinase GCK-3 and the intermediate filament IFB-1, is regulated by ceh-26 (here referred to as pros-1), which we found essential for excretory canal formation. Interestingly, PROS-1 is homologous to vertebrate Prox1, a transcription factor controlling lymphatic vessel growth. Our findings have potential evolutionary implications for the origin of fluid-collecting organs, and provide a reference for lymphangiogenesis.

PubMed

Relationship between angiogenesis and lymphangiogenesis in recurrent pterygium.

2012

Qi CX, Zhang XD, Yuan J, Yang JZ, Sun Y, Wang T, Ye H, Ling SQ.

Source

Department of Ophthalmology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China.

Abstract

AIM:

To examine the relationship between angiogenesis and lymphangigenesis in recurrent pterygia.

METHODS:

Tissues from 34 excised recurrent pterygia (including 12 Grade 1, 10 Grade 2, and 12 Grade 3) were involved in the study and tissues from 7 nasal epibulbar conjunctivae segments were used as controls. Sections from each pterygium were immunostained with CD(31) and LYVE-1 monoclonal antibodies to evaluate lymphatic microvessel density (LMVD) and blood microvessel density (BMVD), and the relationship between LMVD and BMVD in the pterygium was examined.

RESULTS:

There was a large number of CD(31) ((+))LYVE-1((-)) blood vessels but only a few CD(31) ((+))LYVE-1((+))lymphatic vessels in grades 1 and 2 pterygium. However, lymphatic vessels were dramatically increased in grade 3 pterygium. LMVD correlated closely with BMVD in all pterygia, including grades 1, 2 and 3 peterygium patients . Although both the density of blood and lymphatic vessels increased in recurrent pterygia, lymphatic vessels developed much faster than blood vessels, especially in grade 3 pterygia.

CONCLUSION:

 There is a significant but not parallel relationship between angiogenesis and lymphangiogenesis in recurrent pterygium. The outgrowth of blood and lymphatic vessels provide evidence that immunological mechanism may play a role in the development and recurrence of pterygium.

NIH-International Journal of Opthalmology

Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread.

Oct 2012

Ferris RL, Lotze MT, Leong SP, Hoon DS, Morton DL.

Source

Hillman Cancer Center Research, Pavilion 5117 Centre Avenue, Room 2.26b, Pittsburgh, PA, 15213, USA, ferrisrl@upmc.edu.

Abstract

Metastasis to the regional lymph node is the most important prognostic indicator for the outcomes of patients with sold cancer. In general, it is well recognized that cancer development is genetically determined with progression from the microenvironment of the primary tumor site, oftentimes via the SLN gateway, to the distant sites. In about 20 % of the time, the cancer cells may spread directly through the blood vascular system to the distant sites. Thus, in general, cancer progression is consistent with Hellman's spectrum theory in that development of nodal and systemic metastasis from a localized cancer growth is a progressive process. 

Cancer proliferation within the tumor microenvironment may give rise to increased tumor heterogeneity, which is further complicated by its continuous change through its evolution within the host in a Darwinian sense. It is crucial to understand the molecular process of lymphangiogenesis and hemangiogenesis in the tumor microenvironment with respect to the initial steps of cancer cells entering into the lymphatic and vascular systems so that rational therapy can be developed to curb the process of specific routes of metastasis. This chapter elucidates the role of lymphatics, nodal metastasis and antitumor immunity. 

We present novel immune targets in nodal metastases, the importance of the lymph node as a pre-metastatic niche, and immune-related proteins as biomarkers of metastasis.

PubMed

Corneal angiogenesis and lymphangiogenesis.

Oct 2012

Regenfu B, Bock F, Cursiefen C.

Source

Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.

Abstract

PURPOSE OF REVIEW:

The purpose of the present review is to describe new antilymphangiogenic treatment strategies and recent findings on strain-dependency of corneal lymphangiogenesis and the interdependency between blood and lymphatic vessel growth.

RECENT FINDINGS:

Studies on mice have revealed that apart from haemangiogenesis, lymphangiogenesis can also differ markedly between several mouse strains under normal and inflammatory conditions. Although haemangiogenesis and lymphangiogenesis are closely interconnected in their spatial-temporal patterning, recent data suggest that they can also occur independently.

SUMMARY:

Understanding the coordinated regulation of blood and lymphatic vessel growth and genetic factors determining lymphangiogenesis in more detail could improve the development of specifically targeted antihaemangiogenic or antilymphangiogenic strategies.

Lippincott, Wilkins & Williams

Macrophage-Mediated Lymphangiogenesis: The Emerging Role of Macrophages as Lymphatic Endothelial Progenitors.

Sept 2012

Ran S, Montgomery KE.

Source

Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, 801 N. Rutledge, Springfield, IL 62794, USA.

Abstract

It is widely accepted that macrophages and other inflammatory cells support tumor progression and metastasis. During early stages of neoplastic development, tumor-infiltrating macrophages (TAMs) mount an immune response against transformed cells. Frequently, however, cancer cells escape the immune surveillance, an event that is accompanied by macrophage transition from an anti-tumor to a pro-tumorigenic type. The latter is characterized by high expression of factors that activate endothelial cells, suppress immune response, degrade extracellular matrix, and promote tumor growth. Cumulatively, these products of TAMs promote tumor expansion and growth of both blood and lymphatic vessels that facilitate metastatic spread. Breast cancers and other epithelial malignancies induce the formation of new lymphatic vessels (i.e., lymphangiogenesis) that leads to lymphatic and subsequently, to distant metastasis. Both experimental and clinical studies have shown that TAMs significantly promote tumor lymphangiogenesis through paracrine and cell autonomous modes. The paracrine effect consists of the expression of a variety of pro-lymphangiogenic factors that activate the preexisting lymphatic vessels. The evidence for cell-autonomous contribution is based on the observed tumor mobilization of macrophage-derived lymphatic endothelial cell progenitors (M-LECP) that integrate into lymphatic vesselsprior to sprouting. This review will summarize the current knowledge of macrophage-dependent growth of new lymphatic vessels with specific emphasis on an emerging role of macrophages as lymphatic endothelial cell progenitors (M-LECP).

NIH Public Access

Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment.

Aug 2012

Li T, Yang J, Zhou Q, He Y.

Source

Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Thrombosis and Hemostasis Key Lab of the Ministry of Health, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China.

Keywords  Lymphatic endothelial cell – Lymphangiogenesis – Tumor microenvironment – Tumor metastasis

Abstract

A rapid progress has been made in the field of lymphatic research during the last 15 years. This includes better understanding of the cellular events and molecular players involved in the lymphatic vessel formation and remodeling indevelopment. The key players identified in developmental lymphangiogenesis, including vascular endothelial cell growth factor-C (VEGF-C) / VEGFR-3 and angiopoietins (ANGPTs)/ TIE pathways, are also crucial for pathological lymphatic vesselgrowth. In solid tumor, tumor cells as well as tumor-associated stromal cells, such as tumor-infiltrating leukocytes, contribute to intra- and peri-tumoral lymphangiogenesis via secreting lymphangiogenic growth factors. Tumor-associated lymphaticendothelial cells also interact actively with tumor cells and leukocytes via secreting various chemokines. It has been well established that tumor lymphangiogenesis promotes tumor cell dissemination to regional lymph nodes. Thus manipulation of lymphangiogenic microenvironment could become another valuable approach in the combat of tumor progression.

Springerlink

SoxF genes: Key players in the development of the cardio-vascular system.

SoxF genes: Key players in the development of the cardio-vascular system

Francois M, Koopman P, Beltrame M.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.

SoxF genes (Sox7, Sox17 and Sox18) encode a group of transcription factors that have a pivotal role in cardio-vascular development. SOXF factors orchestrate endothelial cell fate or direct cell differentiation in developing heart, blood vessels and lymphatic vessels. Their roles are highly conserved throughout animal evolution. SOXF activity is finely tuned with a variety of cell type-specific co-factors and partner proteins to effect transcription of genes critical for endothelial cell phenotype and function. Because SOXF factors play a central role in cardiogenesis, vasculogenesis and lymphangiogenesis, SOXF gene mutations figure prominently in the aetiology of human vascular disease.

Wiley InterScience

Lymphatic involvement in lymphangioleiomyomatosis.

Lymphatic involvement in lymphangioleiomyomatosis.

Ann N Y Acad Sci. 2008 May
Glasgow CG, Taveira-Dasilva AM, Darling TN, Moss J.
PhD., Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg. 10, Rm. 6D03 MSC 1590, Bethesda, MD 20892-1590. mossj@nhlbi.nih.gov.

Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease affecting primarily premenopausal women. The disease is characterized by cystic lung disease, at times leading to respiratory compromise, abdominal tumors (in particular, renal angiomyolipomas), and involvement of the axial lymphatics (e.g., adenopathy, lymphangioleiomyomas).

Disease results from the proliferation of neoplastic cells (LAM cells), which, in many cases, have a smooth muscle cell phenotype, express melanoma antigens, and have mutations in one of the tuberous sclerosis complex genes (TSC1 or TSC2). In the lung, LAM cells found in the vicinity of cysts are, at times, localized in nodules and may be responsible for cyst formation through the production of proteases.

Lymphatic channels, expressing characteristic lymphatic endothelial cell markers, are found within the LAM lung nodules. LAM cells may also be localized within the walls of the axial lymphatics, and, in some cases, penetrate the wall and proliferate in the surrounding adipose tissue. Consistent with extensive lymphatic involvement in LAM, the serum concentration of VEGF-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers.

Annals of the New York Academy of Sciences

Lymphangiogenesis in development and disease

Lymphangiogenesis in development and disease

Thrombosis and Haemostasis 2007

Ruediger Liersch1, Michael Detmar2
1Department of Medicine, Hematology and Oncology, University Hospital Muenster, Muenster, Germany; 2Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland

Summary

The lymphatic vascular system plays an important role in the maintenance of fluid homeostasis, in the afferent immune response, in the intestinal lipid uptake and in the metastatic spread of malignant cells.The recent discovery of specific markers and growth factors for lymphatic endothelium and the establishment of genetic mouse models with impairment of lymphatic function have provided novel insights into the molecular control of the lymphatic system in physiology and in embryonic development. They have also identified molecular pathways whose mutation- al inactivation leads to human diseases associated with lymphedema. Moreover, the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Importantly, malignant tumors can directly promote lymphangiogenesis within the primary tumor and in draining lymph nodes, leading to enhanced cancer metastasis to lymph nodes and beyond. Based upon these findings, novel therapeutic strategies are currently being developed that aim at inhibiting or promoting the formation and function of lymphatic vessels in disease.

Keywords
Lymphatic endothelium, lymphangiogenesis, lymphedema, inflammation, cancer metastasis

Schattauer

Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin

Overexpression of VEGF-C causes transient lymphatic hyperplasia (lymphedema) but not increased lymphangiogenesis in regenerating skin.

Goldman J, Le TX, Skobe M, Swartz MA. Biomedical Engineering Department, Northwestern University, Evanston, Ill, USA.

Correspondence to Dr Melody A. Swartz, Assistant Professor, Institute for Biological Engineering and Biotechnology, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. E-mail melody.swartz@epfl.ch

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis and holds potential for lymphangiogenic therapy in diseases lacking adequate lymphatic drainage. However, the ability of VEGF-C to enhance sustainable, functional lymphatic growth in adult tissues remains unclear. To address this, we evaluated VEGF-C overexpression in adult lymphangiogenesis in regenerating skin. We used a model of mouse tail skin regeneration incorporating a suspension of either VEGF-C overexpressing tumor cells, which provide a continuous supplement of excess VEGF-C to the natural regenerating environment for more than 25 days, or otherwise identical control- transfected tumor cells. We found that excess VEGF-C did not enhance the rate of lymphatic endothelial cell (LEC) migration, the density of lymphatic vessels, or the rate of functionality -- even though lymphatic hyperplasia was present early on. Furthermore, the hyperplasia disappeared when VEGF-C levels diminished, which occurred after 25 days, rendering the lymphatics indistinguishable from those in control groups. In vitro, we showed that whereas cell-derived VEGF- C could induce chemoattraction of LECs across a membrane (which involves amoeboid-like transmigration), it did not increase LEC chemoinvasion within a 3-dimensional fibrin matrix (which requires proteolytic migration). These results suggest that whereas excess VEGF- C may enhance early LEC proliferation and cause lymphatic vessel hyperplasia, it does not augment the physiological rate of migration or functionality, and by itself cannot sustain any lasting effects on lymphatic size, density, or organization in regenerating adult skin.

AHA Journals

Molecular Biology and Pathology of Lymphangiogenesis

Molecular Biology and Pathology of Lymphangiogenesis

Karpanen T, Alitalo K.
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, FI-00014 Helsinki, Finland t.karpanen@niob.knaw.nl.

Abstract

The lymphatic vasculature is essential for the maintenance of tissue fluid balance, immune surveillance, and adsorption fatty acids in the gut. The lymphatic vessels are also crucially involved in the pathogenesis of diseases such as tumor metastasis, lymphedema, and various inflammatory conditions. Attempts to control or treat these diseases have drawn a lot of interest to lymphatic vascular research during the past few years. Recently, several markers specific for lymphatic endothelium and models for lymphatic vascular research have been characterized, enabling great technical progress in lymphatic vascular biology, and many critical regulators of lymphatic vessel growth have been identified. Despite these significant achievements, our understanding of the lymphatic vessel development and pathogenesis is still rather limited. Several key questions remain to be resolved, including the relative contributions of different pathways targeting lymphatic vasculature, the molecular and cellular processes of lymphatic maturation, and the detailed mechanisms of tumor metastasis via the lymphatic system. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 3 is January 24, 2008. Please see article for revised estimates.

PMID: 18039141 [PubMed - as supplied by publisher]

Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40.

Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40.

Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P.
Section of Pathology, Bellaria Hospital, University of Bologna, Via Altura 3, 40139, Bologna, Italy, f.pedica@alice.it.

Crohn's disease (CD) is a chronic inflammatory bowel disorder of unknown etiology. An involvement of the intestinal lymphatic system has been suggested. Recently, monoclonal antibodies have become available to distinguish lymphatic vessels from blood vessels. The aim of the study was to examine the distribution of lymphatic vessels in ileal and colic walls of patients affected by CD and compare it with healthy controls and other inflammatory bowel diseases. Twenty-eight cases of CD, 13 cases of other inflammatory bowel diseases, and 10 normal ileal and colic walls were studied. Immunohistochemical staining was performed using the monoclonal antibody D2-40. Quantification of lymphatic vessels was performed by identifying four fields with high density of lymphatics and then counting the number of lymphatic vessels at high resolution. Lymphatic diameter was also evaluated by using an ocular micrometer. Lymphatic vessels showed the highest density in CD specimens. The median number of lymphatics was significantly higher both in ileal and colic samples of CD than the other inflammatory diseases as well as normal controls. Moreover, in patients with CD, diffuse lymphangiectasia was also observed. The present data suggest that lymphangiogenesis and lymphangiectasia probably play a role in the pathogenesis of CD.

Springer Link

Pr08 lymphatic malformations and the molecular basis of lymphangiogenesis. Options

Pr08 lymphatic malformations and the molecular basis of lymphangiogenesis.

Options

ANZ J Surg. 2007 May

Ch'ng S, Tan ST. Wellington Regional Plastic Unit, Hutt Hospital, Wellington, New Zealand.
This paper reviews the clinical features of lymphatic malformations and the molecular basis of embryonic lymphangiogenesis.

Lymphatic malformations are classified as microcystic, macrocystic, or combined. Most commonly found in the axilla/chest and cervicofacial region, they can be localised or diffuse. The commonest complications are intralesional bleeding and infection. Other significant complications are due mainly to their mass effect on nearby anatomic structures including the airway and eyeball, and soft tissue and skeletal overgrowth including macrocheilia, macroglossia, macrotia, macromala and mandibular prognathism, resulting in functional problems in feeding, speech, occlusion, oral hygiene, and disfigurement.

The characteristic radiological finding of a LM on gadolinium-enhanced T1-weighted MRI is a low-density lesion with septation or rim enhancement. Histologically, LMs are cystic lesions that contain eosinophilic proteinaceous fluid whose walls are composed of smooth and skeletal muscle fibres, collagen and lymphocytes. Management options range from observation, comfort cares, empirical antibiotic treatment for LM cellulitis to sclerotherapy, surgical excision and Nd:YAG laser for selected cases.

Lymphangiogenesis is believed to occur in four sequential but overlapping stages: lymphatic endothelial cell competence, bias and specification, and finally lymphatic vessel terminal differentiation and maturation. Multiple genes are involved in this process including Lyve1, Nrp2, podoplanin, Prox1, VEGFR3, VEGFC and Ang2. Developmental defects during embryonic lymphangiogenesis result in lymphatic malformations.

PMID: 17490238 [PubMed - in process]